WANTED: New students and postdocs willing to tackle challenging and interesting basic science problems related to human disease (e.g. cancer, aging, prions, etc.).

OUTCOMES: Past lab members have leveraged their training for great positions (see Lab Members tab). Our lab uses a variety of technical approaches to better understand how post-translational modifications regulate the function of CaaX-type proteins. These proteins are subject to an ordered series of C-terminal modifications: isoprenylation (step 1 in the figure below), followed in some cases by proteolysis and carboxylmethylation (steps 2-3). Prominent examples of CaaX proteins can be found among the Ras family of oncoproteins that are often mutated in cancer.

Standard v. Shunt Pathway: We recently discovered that certain CaaX proteins follow an isoprenylation-only branch of the standard modification pathway that we refer to as the shunt pathway (e.g., see Ydj1p in figure below). We are detailing the consequences of altering the modification preference for various CaaX protein reporters, and results indicate that optimal CaaX protein function is linked to pathway preference. These consequences range from altered protein activity, to differential localization, to changes in cellular phenotypes.

The CaaX Proteases: Rce1p and Ste24p are ER membrane-localized proteases. Our research centers on their proteolytic mechanisms, substrate profiles, and biological roles in the cell. We expect to gain a better understanding of their function as gatekeepers for CaaX protein modification via the standard pathway and their utility as targets for disease therapy (e.g. cancer treatment).

The M16A Proteases: Ste23p and Axl1p are zinc-dependent metalloproteases that are part of the M16A subfamily of metalloproteases. They are related to the insulin-degrading enzyme (IDE) that has a proposed protective function in Alzheimer's disease (AD). Our research on Ste23p and Axl1p is designed is to gain a better understanding of the largely uncharacterized M16 metalloprotease family as a whole, thus potentially providing novel insight into new methods for the treatment of AD and possibly other diseases.

The RAS Initiative < Click to learn more about Ras and therapeutic approaches aimed at interfering with Ras biology being developed at The National Cancer Institute.